A recent study of monozygotic twins revealed certain genes and pathways that overlap between post-traumatic stress disorder (PTSD) and migraine, identifying potential drug targets for both disorders.
Post-traumatic stress disorder (PTSD) is a stress-related psychiatric condition that develops after a person experiences a traumatic event. These could be life threats, serious injuries or witnessing death. Although almost 90% of individuals are exposed to a traumatic event during their lifetime, only a small proportion will go on to develop PTSD. The significant variation in risk is thought to be determined by genetic predisposition or epigenetic mechanisms.
One major epigenetic mechanism is DNA methylation. This is a biological process by which methyl groups are added to a DNA molecule, changing the activity of the DNA segment without changing the sequence. One stable epigenetic marker in cells is the addition of a methyl to the cytosine C5 in the cytosine-phosphate-guanine (CpG) dinucleotides of a DNA. Typically, DNA methylation represses gene transcription, especially if it occurs near the promoter region of the gene.
PTSD is often associated with the occurrence of multiple other health conditions, such as depression and coronary heart disease. Migraine is a neurological condition frequently characterised by intense, debilitating headaches. Although many studies have reported a correlation between PTSD and migraine, little is understood about the genes involved.
Using twins to study PTSD and migraine
Recently, a study used a disease-discordant monozygotic (MZ) twin design to explore the genes that overlap in PTSD and migraine. The MZ design is useful when researching the genetic basis of a disease because participants are genetically and demographically matched.
The team performed a genome-wide association study (GWAS) to provide an unbiased approach to identify DNA methylation loci associated with PTSD. This validated 11 candidate genes that were previously linked to PTSD, including DOCK2, DICER1 and ADCYAP1. An epigenome-wide association study (EWAS) then located 7 novel CpG loci that were significantly associated with PTSD, with the principal CpG positioned near gene IL37. Interestingly, this gene has been found to be increased in children with autism.
The genes associated with PTSD were then tested in another sample of MZ twins who suffered from migraine. DAPK2 and TM6SF2 were identified as the two most predominant overlapping genes between the two disorders. DAPK2 has been previously implicated in autophagy. This is an intracellular degradation process that removes unnecessary or dysfunctional components from damaged cells. TM6SF2 has been linked to cardiovascular disease and plays a role in oxidative stress.
Furthermore, it was discovered that adenosine monophosphate-activated protein kinase (AMPK) signalling and regulating pathways were overrepresented for genes associated with both migraine and PTSD. AMPK is an enzyme that plays a role in cellular energy homeostasis.
Potential PTSD drug targets
Overall, these results indicate that common genes and pathways are involved in PTSD and migraine, partly explaining the link between the two disorders. The study also demonstrated that the use of a MZ twin design can provide a useful insight into the epigenetics of complex diseases.
Epigenetic regulation of gene expression is a reversible process and could be an effective pathway to target with drugs. To date, no epigenetic drugs that treat neuropsychiatric disorders or migraine have gone into clinical trials, except one medication called valproate. Nevertheless, further knowledge of linked disorders, such as PTSD and migraine, will aid the development of more advanced pharmacological treatments that target key pathways in both disorders. For example, AMPK pathway activation may be an effective novel therapeutic target for PTSD, or other similar conditions, in the future.
Image credit: FreePik svtdesign
